Background

Lymphangioleiomyomatosis is an ultra-rare disease mainly affecting women of childbearing age. The MILES trial showed the efficacy of sirolimus, an mTOR inhibitor, in stabilising lung function in patients with lymphangioleiomyomatosis. Drug toxicity and development of resistance are potential limitations of therapy with sirolimus. Nintedanib is a multikinase inhibitor that inhibits PDGFR, which is active in human and murine lymphangioleiomyomatosis lesions. We aimed to investigate the activity and safety of nintedanib in patients with lymphangioleiomyomatosis.

Methods

This phase 2, open-label, single-arm study was conducted at MultiMedica IRCCS, a national referral university centre for rare pulmonary diseases in Milan, Italy. Eligible participants were aged 18 years and older and had sporadic or tuberous sclerosis complex-associated lymphangioleiomyomatosis with progressive pulmonary function decline in the past year despite treatment with sirolimus or treatment naive. Patients received nintedanib 150 mg orally twice per day, with a possible reduction to 100 mg twice per day in case of side-effects or hepatoxicity, for 12 months, followed by a period of 12 additional months without study treatment. The primary endpoint was the change in FEV₁ (FEV₁ slope in L) over 12 months. This study is registered with ClinicalTrials.gov, NCT03062943.

Findings

From Oct 14, 2016, to Dec 13, 2019, 35 female patients (mean age 50 years [SD 11]) entered the study, 30 of whom were eligible and received nintedanib. After 12 months, 22 patients completed the treatment, 19 of whom also completed the 12 months of follow-up. FEV₁ remained stable after one year of treatment (predicted mean difference 0·001 L [95% CI –0·063 to 0·066]; p=0·97). During the 12 months off treatment, a slight decline in FEV₁ was observed (predicted mean difference –0·076 L [95% CI –0·149 to –0·004]; p=0·040). The most frequent adverse events were nausea (15 [50%] patients), diarrhoea (eight [26%]), and abdominal pain (two [7%]). No serious adverse events were observed during the treatment period.

Interpretation

Our findings suggest that nintedanib did not improve FEV₁, but that the treatment was generally well tolerated. These results might support nintedanib as a second-line therapy in patients not controlled by standard treatment with mTOR inhibitors. Further investigation, such as a non-inferiority trial comparing nintedanib and sirolimus could help to better clarify the role of this drug as a potential alternative treatment.

Funding

Boehringer-Ingelheim.

中文翻译：

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尼达尼布治疗淋巴管平滑肌瘤病患者：一项 2 期、开放标签、单臂研究

 背景

淋巴管平滑肌瘤病是一种极其罕见的疾病，主要影响育龄妇女。MILES 试验显示了西罗莫司（一种 mTOR 抑制剂）在稳定淋巴管平滑肌瘤病患者肺功能方面的疗效。药物毒性和耐药性的发展是西罗莫司治疗的潜在局限性。Nintedanib 是一种抑制 PDGFR 的多激酶抑制剂，PDGFR 在人和小鼠淋巴管平滑肌瘤病病变中具有活性。我们旨在研究尼达尼布在淋巴管平滑肌瘤病患者中的活性和安全性。

 方法

这项 2 期、开放标签、单臂研究是在意大利米兰的国家罕见肺病转诊大学中心 MultiMedica IRCCS 进行的。符合条件的参与者年龄在 18 岁及以上，尽管接受了西罗莫司治疗或未接受过治疗，但在过去一年中患有散发性或结节性硬化症相关淋巴管平滑肌瘤病伴进行性肺功能下降。患者接受尼达尼布 150 毫克口服，每天两次，如果出现副作用或肝毒性，可能会减少到 100 毫克，每天两次，持续 12 个月，然后再接受 12 个月没有研究治疗。主要终点是 12 个月内 FEV₁ （FEV₁ 斜率以 L 为单位） 的变化。这项研究已在 ClinicalTrials.gov， NCT03062943 注册。

 发现

从 2016 年 10 月 14 日至 2019 年 12 月 13 日，35 名女性患者 （平均年龄 50 岁 [SD 11]）进入研究，其中 30 名符合条件并接受了尼达尼布治疗。12 个月后，22 名患者完成了治疗，其中 19 名还完成了 12 个月的随访。FEV₁ 在治疗一年后保持稳定 （预测平均差 0·001 L [95% CI –0·063 至 0·066];p = 0·97）。在停止治疗的 12 个月期间，观察到 FEV₁ 略有下降（预测平均差 -0·076 L [95% CI -0·149 至 -0·004];p=0·040）。最常见的不良事件是恶心 （15 [50%] 患者）、腹泻 （8 [26%]）和腹痛 （2 [7%]）。治疗期间未观察到严重不良事件。

 解释

我们的研究结果表明，尼达尼布没有改善 FEV₁，但治疗总体耐受性良好。这些结果可能支持尼达尼布作为 mTOR 抑制剂标准治疗未控制的患者的二线治疗。进一步的研究，例如比较尼达尼布和西罗莫司的非劣效性试验，可能有助于更好地阐明该药物作为潜在替代治疗的作用。

 资金

 勃林格殷格翰。